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If there is one factor common to genetic association studies it is their heterogeneity
Bertram
and Tanzi 2004Shi
et al, 2008 Dozen of confusing positive and negative studies blur the picture
and suggest that many are related to artefact or insufficient statistical power.
However, while at a global level these results are contentious, at a local level
they can be quite homogenous, tending to cluster in positive or negative association
hot and coldspots around the world.These examples are taken from data from the
Alzgene and Szgene databases and are posted to illustrate this phenomenon.

This was done gene by gene, rather than by individual polymorphism, but this
clustering could relate to several possibilities. Firstly, all polymorphisms/mutations
have a single ancestral origin in a particular place at a particular time. For
example a presenilin mutation has been tracked back to a family in Southern
Italy prior to the 17th century Bruni
at al, 2010 Their spread around the world will depend on their success (natural
selection), their age and the migratory patterns of their bearers. Conquests,
forced and voluntary expatriation will influence their distribution. Secondly,
environmental factors may influence the risk promoting effects of many genes.
For example many Alzheimer's disease related genes are related to cholesterol
and lipoprotein function, and many related risk factors See
risk factors (high cholesterol, saturated fat consumption) and protective
factors (fish diets, polyunsaturated fat consumption, Mediterranean diet) may
influence whether or not these genes are risk promoting. High fat consumption
and APOE polymorphisms are a dangerous mix, but perhaps APOE is less risk promoting
in countries with a high fish consumption (see negative APOE data from Japan).
Thirdly, certain genes may also be related to infectious agents Carter
2009Prasad
et al, 2010 whose distribution varies around the globe. Each of these could
influence positive and negative association data, which at a local level do
not seem to be so heterogeneous.

Positive results are represented by filled black circles and negative
results by open circles

Clusterin: Note the negative data from Spain and from a US study of
Hispanic patients

Angiotensin converting enzyme ACE

No positive associations between MTHFR and Alzheimer’s disease have been
reported in any European region. Positive association is exclusively localised
to Iran, China and Korea,

and to an NIMH
study in the USA. Maryland
(the seat of NIMH) has a high proportion of Korean immigrants.

SORL1 sortilin-related receptor, L(DLR class)

APOE

COMT

Illinois
settlers (mainly negative data) were originally French, German and Swedish ,
those in Minnesota,
German and Nordic, and those in Iowa
mainly French.. With the exception of 1 positive German study, most of these
European areas return negative association data for COMT. In contrast, the population
of Maryland
derives from Latin America (and thus Spain), Asia and Korea, all of which
possess fairly dense clusters of positive association data. Baltimore,
Pittsburgh
and New
York are large multicultural cites, displaying both positive and negative
association data.